The basic living unit of the body is the cell, and each organ is an aggregate of many different cells held together by intercellular supporting structures. In the interstitial fluid (ISF) are the nutrients needed by the cells for maintenance of cellular life. One of the essential nutrients is protein (mainly albumin). Albumin binding water and electrolytes slow down entry of water and electrolytes into cell body, hence protecting the cells from swelling. Swelling may be thought of as the common pathway for all kinds of cellular damage, including hypoxia, ischemia, trauma, poisoning, infection etc.
Although the ISF derives from the blood, the concentration of protein in the ISF is always lower than that in the blood, about 7.3 gram/dl in plasma versus 2 to 3 gram/dl in the ISF. This is because that blood capillaries are only partially permeable to plasma protein. The ISF in central nervous system (CNS) contains the lowest concentration of protein (about 25 mg/dl), because of the blood brain barrier (BBB) and blood-cerebrospinal fluid barriers. As a result, cells in the bloodstream are more tolerant than cells in peripheral organ system, and cells in the peripheral organ system are much more tolerant than cells in the CNS.
In the capillaries of peripheral organ systems, adjacent endothelial cells form an intercellular cleft, which normally has a uniform spacing with a width of about 6 to 7 nanometers. The molecular weight of albumin is about 68,000 D, its diameter size is slightly larger than 7 nanometers. In addition, the endothelium and surrounding basement membrane are negatively charged, owing to the presence of exposed acidic residues. Proteins are amphoteric molecules carrying positive, negative, or neutral charges depending on the local pH environment. The net charge of a protein is the sum of all the negative and positive charges of its amino acid side chains, and its amino- and carboxyl-termini. The isoelectric point (pI) is the specific pH at which the net charge of the protein is zero. At a pH below the pI, proteins carry a net positive charge and vice-versa. Native albumin has a pI of about 4-4.8, and is therefore negatively charged at physiological pH. As a result, there is a rejective action between endothelium and albumin. Nevertheless, the ISF contains about 2-3 gram/dl of albumin in peripheral organ systems.
However, in the CNS, cerebral capillary endothelial cells are bound together with ‘tight junctions’, and the endothelium and basement membrane are strongly negatively charged. This forms the BBB and blood-cerebrospinal fluid barrier, which prevent albumin from entering the ISF and cerebrospinal fluid, and as a result, the ISF and the cerebrospinal fluid in the CNS only contain about 25 mg/dl of albumin.
In clinic, intravenous albumin injection has been used for treating various injuries. However, due to its large molecular weight and low pI, albumin does not easily enter the ISF to function. Substances of large molecular weight trend to increase fluid viscosity. High concentrations of albumin inside the blood stream lead to an increase of blood volume which may result in a heavy burden on the heart resulting in pulmonary edema. Therefore, intravenous albumin injection has had limited effect in protecting tissue.